The present invention relates to a controlled drug release system in which a certain ratio of retinoic acid (herein after referred to as xe2x80x9cRAxe2x80x9d) is incorporated into a microsphere comprising biodegradable polymer and amphiphilic copolymer having both hydrophilic and hydrophobic groups.
Retinoic acid has been known to have roles in controlling the differentiation and growth of cells and reportedly inhibits carcinogenesis in various epithelial tissues. It has especially been known to have good effects on the prevention and treatment of cancers such as head and neck cancer, skin cancer, lung cancer, breast cancer, cervical cancer, bladder cancer, etc. and also exhibits efficacy in patients suffering from acute promyelocytic leukemia [See, Blood 76, 1704-1709 (1990), Blood 78, 1413-1419 (1991); and, The New England Journal of Medicine 324, 1385-1393 (1991)].
However, upon continuous repetitive administration of retinoic acid, drug level in blood is rapidly decreased compared with the early stage of treatment [Blood 79, 299-303 (1992)], and the diseases are recurred within a short period [Cancer Research 52, 2138-2142 (1992)]. This is because the oral administration of retinoic acid induces cytochrome P450 enzyme which metabolizes retinoic acid. Even in a case where a small amount of retinoic acid is administered, cytochrome P450 is induced, and repeated administration would accelerate the metabolism by the enzyme and thus it is impossible to maintain effective retinoic acid level in blood. If the level of retinoic acid increases, severe side toxic effects would appear, and even result in difficulty in breathing, spasm, comatose state which leads to death. In order to solve these problems, drug release systems for retinoic acid using liposome [Leukemia Research 18, 587-596 (1994)] or nanoparticle [International Journal of Pharmaceutics 131, 191-200 (1996)] have been tried, but these systems have a drawback that the control of drug release is difficult.
As another prior art reference for delayed retinoic acid release system, it has been reported that retinoic acid was released over 40 days by incorporating retinoic acid into a microsphere prepared from lactic acid and poly(lactic-co-glycolic acid), (hereinafter referred to as xe2x80x9cPLGAxe2x80x9d) [see, investigative Ophthalmology and Visual Science 34, 2743-3751 (1993)]. The system was focused on the treatment of proliferative vitreoretinopathy. However, the microsphere prepared by this technique has a drawback that it is difficult to be dispersed into an aqueous phase. In addition, since ethylene oxide is impossible for applying gas sterilization, gamma-ray sterilization should be used. Even if, such gamma-ray sterilization is carried out on the microsphere, the molecular weight thereof is decreased. Further, this prior art system fails to teach the use of amphiphilic copolymer in controlling the dissolution rate of the microsphere and the release rate of retinoic acid.
It is therefore an object of the present invention to solve the problems associated with the prior art release system.
Another object of the present invention is to provide a controlled drug release system for retinoic acid which comprises microsphere in which the biodegradable polymer and amphiphilic block copolymer and retinoic acid incorporated into the microsphere.
Further objects and advantages of the invention will become apparent through reading the remainder of the specification.
The foregoing has outlined some of the more pertinent objects of the present invention. These objects should be construed to be merely illustrative of some of the more pertinent features of the invention. Many other beneficial results can be obtained by applying the disclosed invention in a different manner or by modifying the invention within the scope of the disclosure. Accordingly, other objects and a more thorough understanding of the invention may be found by referring to the detailed description of the preferred embodiment in addition to the scope of the invention defined by the claims.